The patient underwent pancreaticoduodenectomy, which showed a 5.0 cm well circumscribed mass confined in the head of the pancreas. The cut surface of the tumor is tan, soft with mixed areas of necrosis and hemorrhage. The following images (Figure 1-4) are representative micrographs of the tumor.

Figures 1- 4 show representive images from the solid areas of tumor that are composed of uniform, non-cohesive polygonal cells intermixed with foamy histiocytes and many atypical multinucleated giant cells. The mononuclear tumor cells have eosinophilic cytoplasm with uniform, round to oval nuclei, finely stippled chromatin and low nuclei to cytoplasm (N/C) ratio. The atypical giant cells have multiple, markedly enlarged, hyperchromatic nuclei with smudged chromatin. Mitoses are rare. Nuclear grooves are present in some of the mononuclear cells. Area of pseudopapillae, intracytoplasmic vacuoles, eosinophilic globules and cholesterol crystals with foreign body giant cell reaction are present. Both mononuclear and atypical multinucleated giant cells are positive for β-catenin, progesterone receptor (PR) and vimentin, but are negative for pan-cytokeratin, synaptophysin, chromogranin, CD68, and trypsin. The tumor has a Ki-67 labeling index of less than 1%. The foamy histiocytes are positive for CD68.

Discussion

Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor with low-grade malignant potential, accounting for approximately 1–3% of all pancreatic tumors (1-3). SPN occurs predominantly in young females in their 20s and 30s with a female to male ratio of 9:1 (2). The patients often presented with nonspecific, abdominal mass-related symptoms such as abdominal pain, early satiety etc. A recent study showed that up to 9% of asymptomatic pancreatic incidentalomas discovered by physical examination or abdominal imaging studies performed for other reasons are SPNs (4). Complete surgical resection is often curative and the prognosis for patients with SPN is very good with a 5-year survival rate of more than 90%. Hoewever, 10–15% of patients may develop recurrent SPN, liver or peritoneal metastases after surgical resection (5-8). Muscular vessel invasion and tumor stage have been shown to be important predictors of disease-specific survival in patients with SPN (9).

Grossly, SPNs are well circumscribed, often large masses with a average tumor size of 9 to 10 cm. The cut surface of SPN is soft and heterogeneous, consisting of tan to yellow solid areas, irregular areas of necrosis with cavities (cystic areas) and hemorrhagic areas. Histologically, the solid area of conventional SPN are characterized by the presence of numerous capillaries or delicate small blood vessels with variable amounts of hyalinized or myxiod stroma forming the vascular cores, which are surrounded by relatively uniform, non-cohesive polygonal cells to form the pseudopapillae. The nuclei of the tumor cells are located away from the vascular cores creating a zone of cytoplasm around the vescular cores. At the peripheries of the pseudopapillae, the tumor cells are often detached. The tumor cells have uniform, round to oval nuclei with finely stippled chromatin pattern, frequent nuclear grooves and low nuclei to cytoplasm (N/C) ratio. Mitoses are rare or absent. The cytoplasm is eosinophilic or clear. Intracytoplasmic vacuoles or periodic acid-Schiff (PAS)-positive diastase-resistant eosinophilic globules, foamy histiocytes and cholesterol crystals with foreign body giant cell reaction are commonly present in SPN.

SPNs are typically positive for β-catenin mutations, but negative for mutations in oncogenic Kras gene. Nuclear staining of β-catenin by immunohistochemistry has been widely used as one of the diagnostic markers for SPN (10, 11). SPNs are also positive for progesterone receptor (PR), SOX11, Transcription factor E3 (TFE3), alpha-1-antitrysin, vimentin, CD10, cyclin D1, neuron-specific enolase (NSE), CD56, and are negative for CK7, CK19, epithelial membrane antigen (EMA), carcinoembrynonic antigen (CEA), chromogranin, estrogen receptor (ER), BCL10, trypsin, and lipase. SPNs typically show either negative or weak/patch staining for cytokeratin AE1/AE3 and CAM5.2 and synaptophysin, and has a low Ki-67 labeling index (typically less than 2%).

Atypical multinucleated giant tumor cells have been reported in four (6.5%) SPN patients in a large cohort of 62 patients (12) and one (5%) of 20 patients (13), respectively. All four patients who have SPN with atypical multinucleated giant tumor cells in the study published by Li et al. were discovered incidentally by imaging studies for unrelated diseases and have a female to male ratio of 1:1 and a mean age of 51.3 years (range 36–59 years) at the time of diagnosis, which is significantly older than those with conventional SPN (mean age: 32.1 years, range: 9.4–62.2 years). The tumor is more likely located in the head of the pancreas (12). The atypical giant tumor cells present in the solid area of the tumor have multiple enlarged, hyperchromatic, irregular nuclei with smudged chromatin, ample eosinophilic or clear cytoplasm, which raise the concern of aggressive clinical behavior or high-grade malignancy. However these atypical multinucleated giant tumor cells have an immunohistochemical profile identical to the conventional SPN and are positive for vimentin, β-catenin, CD10 and progesterone receptor, but negative for pan-cytokeratin, chromogranin, synaptophysin, trypsin, Ki-67 and CD68 (12-14), which argue against a histiocytic origin of these giant cells. All four cases of SPN with atypical multinuclear giant tumor cells have a proliferation index (Ki-67) of <1%, which is typically seen in conventional SPNs. None of the three patients who had SPNs with atypical multinuclear giant tumor cells developed recurrence during follow-up of 2.7, 3.8 and 5.0 years. Therefore the presence of atypical multinuclear giant tumor cells in SPN most likely represents degenerative change of the tumor cells and does not seem to affect the prognosis based on the limited number of patients from this study (12). The similar degenerative nuclear atypia has also been reported in pleomorphic pancreatic neuroendocrine tumors,(15) symplastic leiomyomas,(16) symplastic glomus tumor,(17) symplastic haemangioma(18) and bizarre giant cells of mammary fibroadenomas (19).

The clear cell variant of SPN and two rare cases of clinically aggressive SPNs have also been reported in the literature. The clear cell variant of SPN has the similar clinical features, gross characteristics and immunohistochemical staining profile to those of conventional SPNs (20-22). The two cases of clinically aggressive SPNs, consisting of conventional SPN and an undifferentiated carcinoma component, which had a diffuse growth pattern, extensive tumor necrosis, significant nuclear atypia, and high mitotic count, have been reported. Both patients died of disease at 6 and 16 months after diagnosis, respectively (23).

The major differential diagnoses for SPN with atypical multinucleated giant tumor cells include pleomorphic pancreatic neuroendocrine tumor, undifferentiated carcinoma, and undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, pancreatoblastoma, and mixed acinar-neuroendocrine carcinoma. Pancreatic neuroendocrine tumor, acinar cell carcinoma, mixed acinar-neuroendocrine carcinoma, and pancreatoblastoma may have overlapping nuclear and cytologic features with SPN. However, the presence of pseudopapillae, foamy histiocytes, cholesterol crystals and intracytoplasmic eosinophilic globules favor the diagnosis of SPN. Squamoid nests, which are the diagnostic hallmark for pancreatoblastoma, is not present in SPN. Acinar cell carcinoma, undifferentiated carcinoma, and undifferentiated carcinoma with osteoclast-like giant cells are cohesive, pleomorphic high-grade carcinomas with frequent mitoses and may have focal lumen or glandular formation. On the other hand, the tumor cells in convertional SPN are discohesive and lack high-grade nuclear features, mitosis and lumen or glandular formation. The osteoclast-like giant cells in undifferentiated carcinoma are of histiocytic origin (positive for CD68) and lack the expression of PR and nuclear β-catenin. Given the above-mentioned unique immunohistochemical profile of SPN, a panel of immunohistochemical markers, including pan-cytokeratin, β-catenin, CD10, PR, chromogranin, synaptophysin, trypsin or chymotrypsin and BCL10 is rerecommended to establish the correct diagnosis. Since most SPNs express NSE, CD56, and alpha-1-antitrypsin, these markers are not useful in the differential diagnosis between SPN and pancreatic neuroendocrine tumor or acinar cell carcinoma.